Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies

Abstract

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0504-y) contains supplementary material, which is available to authorized users.

Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

“…The results presented here demonstrate that anle138b treatment is beneficial in early‐stage MSA as modeled by young PLP‐hαSyn mice . However, efficacy of anle138b was less prominent in a model of pathologically advanced MSA .…”

“…Microglial activation and neuroinflammation constitute important pathological features of MSA . Similarly to the human pathology, PLP‐hαSyn mice develop progressive microglial activation, initially triggered by α‐syn pathology in a region‐specific manner . In a recent publication from our group, significant microglial activation was observed in the SN of MSA transgenic mice compared to healthy control animals at 5 months of age, and this activation was linked to abnormal neuroinflammatory response .…”

“…Similarly to the human pathology, PLP‐hαSyn mice develop progressive microglial activation, initially triggered by α‐syn pathology in a region‐specific manner . In a recent publication from our group, significant microglial activation was observed in the SN of MSA transgenic mice compared to healthy control animals at 5 months of age, and this activation was linked to abnormal neuroinflammatory response . PLP‐hαSyn mice also develop progressive SND characterized by a 30% reduction in the number of dopaminergic neurons (tyrosine hydroxylase positive [TH + ] neurons) in the SNc compared to healthy control animals.…”

“…The Parkinson's variant or MSA‐P is characterized by striatonigral degeneration (SND), whereas the cerebellar variant or MSA‐C reflects olivopontocerebellar atrophy (OPCA) . The PLP‐hαSyn transgenic mouse model recapitulates most of the clinical and pathophysiological features of MSA by overexpressing human α‐syn under the oligodendrocyte PLP (myelin proteolipid protein) promoter, which leads to GCI formation, microglial activation, and selective neurodegeneration …”

“…PLP‐hαSyn mice also develop progressive SND characterized by a 30% reduction in the number of dopaminergic neurons (tyrosine hydroxylase positive [TH + ] neurons) in the SNc compared to healthy control animals. This neuronal loss is already present at 4 months of age and is followed by a significant reduction in density of dopaminergic terminals and in number of medium spiny neurons in the striatum at 12 months of age . SN and striatum are both essential for motor control, and the loss of neurons in these two brain areas leads to motor impairment in these mice …”